Endocrine hormones and local signaling pathways contribute to the formation and progression of breast, uterine, and prostate carcinomas. In addition, many of the same growth factor receptors and their corresponding downstream kinases that function in development or hormone action also contribute to the growth and metastasis of cancer cells. For example, overexpression or amplification of ErbB-2 occurs in 20-30% of human breast carcinomas. In a related study, we found that transcripts for heregulin, a ligand for ErbB-3 or ErbB-4, were found in all samples of mammary adenocarcinomas obtained from mice carrying either the MMTV-Wnt-1 or MMTV (activated) ErbB-2 transgene; heregulin transcripts were also in mammary adenocarcinomas of mice exposed to various chemical carcinogens. We failed to detect heregulin mRNA in the mammary glands of adult virgin mice. Since extracts of tumors from the Wnt-1 transgenics contained the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) bound to ErbB-3, it is conceivable that the expression of the heregulin ligand stimulates an autocrine or paracrine circuit that may contribute to tumor development. We are currently performing in vitro experiments to determine whether heregulin does account for the activation of ErbB-3 in mammary tumor cells. Elevated serum IGF-1 is associated with an increased risk of breast and prostate carcinomas. We examined glands of IGF-1-deficient mice during mammary development (branching morphogenesis). Female mice with a null mutation (IGF-1-/-) develop only a mammary rudiment, whereas mice that exhibit a partial reduction in the formation of IGF-1 (IGF-1m/m or "midi" mice) exhibit diminished branching when compared to that of wild-type littermates. The ducts of the "midi" mouse did extend to the limits of the fat pad. These mouse models allow us to speculate that the extent of mammary ductal branching is regulated by the activity of the epithelial IGF-1 receptor at the time of gland morphogenesis. We have also tried to understand the role of IGF-1 in the estrogen-stimulated proliferation of mouse uterine epithelial cells. Estrogen-treated mice with a null mutation for IGF-1 or the insulin receptor substrate (IRS) -1 exhibited the normal level of DNA synthesis in the uterine epithelium; however, the rate of mitosis and cdk-1/cyclinB kinase were markedly lower in the mutants, indicating that IGF-1 specifically affects G2 -> M transition of the cell cycle. These studies also indicate that the effects of IGF-1 on uterine cell proliferation are mediated through the IRS-1 adaptor protein. We also showed that IRS-1 is stable throughout the cell cycle, whereas IRS-2 almost totally disappears by ~20 hours after estrogen exposure as a consequence of IGF-1 receptor-mediated proteasomal degradation.